Low back pain (LPB) is the main cause of disability worldwide with enormous socioeconomic burdens. A major cause of LBP is intervertebral disc degeneration (IDD): a chronic, progressive process associated with exhaustion of the resident cell population, tissue inflammation, degradation of the extracellular matrix and dehydration of the nucleus pulposus. Eventually, IDD may lead to serious sequelae including chronic LBP, disc herniation, segmental instability, and spinal stenosis, which may require invasive surgical interventions. However, no treatment is actually able to directly tackle IDD and hamper the degenerative process. In the last decade, the intradiscal injection of stem cells is raising as a promising approach to regenerate the intervertebral disc. This review aims to describe the rationale behind a regenerative stem cell therapy for IDD as well as the effect of stem cells following their implantation in the disc environment according to preclinical studies. Furthermore, actual clinical evidence and ongoing trials will be discussed, taking into account the future perspective and current limitations of this cutting-edge therapy.
A literature analysis was performed for this narrative review. A database search of PubMed, Scopus and ClinicalTrials.gov was conducted using “stem cells” combined with “intervertebral disc”, “degeneration” and “regeneration” without exclusion based on publication date. Articles were firstly screened on a title-abstract basis and, subsequently, full-text were reviewed. Both preclinical and clinical studies have been included.
The database search yielded recent publications from which the narrative review was completed.
Based on available evidence, intradiscal stem cell therapy has provided encouraging results in terms of regenerative effects and reduction of LBP. However, multicenter, prospective randomized trials are needed in order confirm the safety, efficacy and applicability of such a promising treatment.
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Purpose of review: Regenerative medicine through interventional pain procedures is evolving with data demonstrating efficacy for a number of pain states in recent years. Platelet-rich plasma (PRP), defined as a sample of plasma with a platelet concentration 3 to 5 times greater than the physiologic platelet concentration found in healthy whole blood, releases bioactive proteins which can restore anatomical function in degenerative states. PRP is dense in growth factors, such as platelet-derived growth factor, transforming growth factor-beta1, basic fibroblastic growth factor, vascular endothelial growth factor, and epidermal growth factors.
Recent findings: To date, well-designed case-control or cohort studies for the use of PRP have demonstrated efficacy in lumbar facet joint, lumbar epidural, and sacroiliac joint injections. At present, there is only level IV evidence indicating the need for larger and more carefully controlled prospective studies. PRP is utilized autogenously in order to facilitate healing and injection and has been studied in the long-term management of discogenic low back pain. In this regard, numerous studies have evaluated PRP to steroid injections in chronic pain states with favorable results. PRP represents an opportunity for a new strategy in the therapeutic treatment of degenerative states of spines, joints, and other locations throughout the body with evolving data demonstrating both safety and long-term efficacy.
To learn more about these treatments, please contact Miami Stem Cell (305) 598-7777 or by visiting: www.stemcellmia.com
A novel off-the-shelf bio-implant containing embryonic stem cells has the potential to revolutionize the treatment of cartilage injuries
More than a million Americans undergo knee and hip replacements each year. It’s a last resort treatment for pain and mobility issues associated with osteoarthritis, a progressive disease caused by degeneration of the protective layer of cartilage that stops our bones grinding together when we sit, stand, write, or move around.
But what if doctors could intervene and repair damaged cartilage before surgery is needed?
For the first time, researchers at the Keck School of Medicine of USC have used a stem cell-based bio-implant to repair cartilage and delay joint degeneration in a large animal model. The work will now advance into humans with support from a $6 million grant from the California Institute of Regenerative Medicine (CIRM).
The research, recently published in npj Regenerative Medicine, was led by two researchers at the Keck School of Medicine of USC: Denis Evseenko, MD, PhD, associate professor of orthopaedic surgery, and stem cell biology and regenerative medicine, director of the skeletal regeneration program, and vice chair for research of orthopaedic surgery; and Frank Petrigliano, MD, associate professor of clinical orthopaedic surgery and chief of the USC Epstein Family Center for Sports Medicine.
Osteoarthritis occurs when the protective cartilage that coats the ends of the bones breaks down over time, resulting in bone-on-bone friction. The disorder, which is often painful, can affect any joint, but most commonly affects those in our knees, hips, hands and spine.
To prevent the development of arthritis and alleviate the need for invasive joint replacement surgeries, the USC researchers are intervening earlier in the disease.
“In some patients joint degeneration starts with posttraumatic focal lesions, which are lesions in the articular (joint) cartilage ranging from 1 to 8 cm2 in diameter,” Evseenko said. “Since these can be detected by imaging techniques such as MRI, this opens up the possibility of early intervention therapies that limit the progression of these lesions so we can avoid the need for total joint replacement.”
That joint preservation technology developed at USC is a therapeutic bio-implant, called Plurocart, composed of a scaffold membrane seeded with stem cell-derived chondrocytes—the cells responsible for producing and maintaining healthy articular cartilage tissue. Building on previous research to develop and characterize the implant, the current study involved implantation of the Plurocart membrane into a pig model of osteoarthritis. The study resulted in the long-term repair of articular cartilage defects.
“This is the first time an orthopaedic implant composed of a living cell type was able to fully integrate in the damaged articular cartilage tissue and survive in vivo for up to six months,” Evseenko said. “Previous studies have not been able to show survival of an implant for such a long time.”
Evseenko said molecular characterization studies showed the bio-implant mimicked natural articular cartilage, with more than 95 percent of implanted cells being identified as articular chondrocytes. The cartilage tissue generated was also biomechanically functional—both strong enough to withstand compression and elastic enough to accommodate movement without breaking.
With support from the $6 million translational grant from CIRM, the researchers are using this technology to manufacture the first 64 Plurocart implants to be tested in humans.
“Many of the current options for cartilage injury are expensive, involve complex logistical planning, and often result in incomplete regeneration,” said Petrigliano. “Plurocart represents a practical, inexpensive, one-stage therapy that may be more effective in restoring damaged cartilage and improve the outcome of such procedures.”
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Stopping arthritis before it starts
Making stem cells from a patient’s adult cells – rather than human embryos – is one of the holy grails in modern medicine treatments. New research brings us two steps closer.
Biomedical engineers and medical researchers at UNSW Sydney have independently made discoveries about embryonic blood stem cell creation that could one day eliminate the need for stem cell blood donors.
The achievements are part of a move in regenerative medicine towards the use of ‘induced pluripotent stem cells’ to treat disease, where stem cells are reverse engineered from adult tissue cells rather than using live human or animal embryos.
But while we have known about induced pluripotent stem cells since 2006, scientists still have plenty to learn about how cell differentiation in the human body can be mimicked artificially and safely in the lab for the purposes of delivering targeted medical treatment.
Two studies have emerged from UNSW researchers in this area that shine new light on not only how the precursor blood stem cells occur in animals and humans, but how they may be induced artificially.
In a study published today in Cell Reports, researchers from UNSW School of Biomedical Engineering demonstrated how a simulation of an embryo’s beating heart using a microfluidic device in the lab led to the development of human blood stem cell ‘precursors’, which are stem cells on the verge of becoming blood stem cells.
And in an article published in Nature Cell Biology recently, researchers from UNSW Medicine & Health revealed the identity of cells in mice embryos responsible for blood stem cell creation.
Both studies are significant steps towards an understanding of how, when, where and which cells are involved in the creation of blood stem cells. In the future, this knowledge could be used to help cancer patients, among others, who have undergone high doses of radio- and chemotherapy, to replenish their depleted blood stem cells.
Emulating the heart
In the study detailed in Cell Reports, lead author Dr Jingjing Li and fellow researchers described how a 3cm x 3cm microfluidic system pumped blood stem cells produced from an embryonic stem cell line to mimic an embryo’s beating heart and conditions of blood circulation.
She said that in the last few decades, biomedical engineers have been trying to make blood stem cells in laboratory dishes to solve the problem of donor blood stem cell shortages. But no one has yet been able to achieve it.
“Part of the problem is that we still don’t fully understand all the processes going on in the microenvironment during embryonic development that leads to the creation of blood stem cells at about day 32,” Dr Li said.
“So we made a device mimicking the heart beating and the blood circulation and an orbital shaking system which causes shear stress – or friction – of the blood cells as they move through the device or around in a dish.”
These systems promoted the development of precursor blood stem cells which can differentiate into various blood components – white blood cells, red blood cells, platelets and others. They were excited to see this same process – known as haematopoiesis – replicated in the device.
Study co-author Associate Professor Robert Nordon said he was amazed that not only did the device create blood stem cell precursors that went on to produce differentiated blood cells, but it also created the tissue cells of the embryonic heart environment that is crucial to this process.
“The thing that just wows me about this is that blood stem cells, when they form in the embryo, form in the wall of the main vessel called the aorta. And they basically pop out of this aorta and go into the circulation, and then go to the liver and form what’s called definitive haematopoiesis, or definitive blood formation.
“Getting an aorta to form and then the cells actually emerging from that aorta into the circulation, that is the crucial step required for generating these cells.”
“What we’ve shown is that we can generate a cell that can form all the different types of blood cells. We’ve also shown that it is very closely related to the cells lining the aorta – so we know its origin is correct – and that it proliferates,” A/Prof. Nordon said.
The researchers are cautiously optimistic about their achievement in emulating embryonic heart conditions with a mechanical device. They hope it could be a step towards solving challenges limiting regenerative medical treatments today: donor blood stem cell shortages, rejection of donor tissue cells, and the ethical issues surrounding the use of IVF embryos.
“Blood stem cells used in transplantation require donors with the same tissue-type as the patient,” A/Prof. Nordon said.
“Manufacture of blood stem cells from pluripotent stem cell lines would solve this problem without the need for tissue-matched donors providing a plentiful supply to treat blood cancers or genetic disease.”
Dr Li added: “We are working on up-scaling manufacture of these cells using bioreactors.”
Meanwhile, and working independently of Dr Li and A/Prof. Nordon, UNSW Medicine & Health’s Professor John Pimanda and Dr Vashe Chandrakanthan were doing their own research into how blood stem cells are created in embryos.
In their study of mice, the researchers looked for the mechanism that is used naturally in mammals to make blood stem cells from the cells that line blood vessels, known as endothelial cells.
“It was already known that this process takes place in mammalian embryos where endothelial cells that line the aorta change into blood cells during haematopoiesis,” Prof. Pimanda said.
“But the identity of the cells that regulate this process had up until now been a mystery.”
Read more: Baby mice have a skill that humans want – and this microchip might help us learn it
In their paper, Prof. Pimanda and Dr Chandrakanthan described how they solved this puzzle by identifying the cells in the embryo that can convert both embryonic and adult endothelial cells into blood cells. The cells – known as ‘Mesp1-derived PDGFRA+ stromal cells’ -– reside underneath the aorta, and only surround the aorta in a very narrow window during embryonic development.
Dr Chandrakanthan said that knowing the identity of these cells provides medical researchers with clues on how mammalian adult endothelial cells could be triggered to create blood stem cells – something they are normally unable to do.
“Our research showed that when endothelial cells from the embryo or the adult are mixed with ‘Mesp1 derived PDGFRA+ stromal cells’ – they start making blood stem cells,” he said.
While more research is needed before this can be translated into clinical practice – including confirming the results in human cells – the discovery could provide a potential new tool to generate engraftable haematopoietic cells.
“Using your own cells to generate blood stem cells could eliminate the need for donor blood transfusions or stem cell transplantation. Unlocking mechanisms used by nature brings us a step closer to achieving this goal,” Prof. Pimanda said.
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Scientists at the Francis Crick Institute have identified a group of latent stem cells that respond to injury in the central nervous system of mice. If a similar type of cell exists in humans, they could offer a new therapeutic approach to treat brain and spinal cord injuries.
After disease or injury, stem cells help repair the damage by replacing cells that have died. In some organs, like the skin and intestine, these stem cells are constantly active, while in others, so called ‘latent stem cells’ lie waiting for harm to occur before being triggered into action.
In their study published in Developmental Cell today (Monday 22 August), the researchers identified a group of latent stem cells in the central nervous system of mice. These are part of the ependymal cells that line the walls of compartments in the brain and spinal cord that hold cerebrospinal fluid.
The cells were identified by chance when the team used a fluorescence tool to look for immune cells called dendritic cells in the brain. The ependymal cells that the tool identified were found to arise from embryonic progenitor cells that shared a same protein as dendritic cells on their surface, which revealed them to the scientists.
Working with neuroscientist colleagues at the Francis Crick Institute and developmental biologists at the Institute of Molecular Medicine in Lisbon, they found that in healthy mice, these cells stay still and waft small hairs on their surface to help the flow of cerebrospinal fluid.
However, in injured mouse spinal cords, these cells responded by dividing, migrating towards the damaged area and differentiating into astrocytes, one of the major cell types of the nervous system. The team also looked at these cells in detail in the lab and found they demonstrated key hallmarks of stem cell behaviour. They divided continuously over a long period of time, and were also able to differentiate into all three main cell types of the central nervous system — neurons, astrocytes and oligodendrocytes.
Bruno Frederico, co-corresponding author and postdoctoral training fellow in the Immunobiology laboratory at the Crick says, “While we don’t know if these cells exist in humans, if they do, it would be interesting to see if they also default to becoming astrocytes rather than neurons in response to damage. This might help explain why the mammalian central nervous system does not have a strong ability to repair itself after injury.
“If we could find a way to overcome the barriers that are stopping the differentiation into neurons and oligodendrocytes after spinal cord injury, it could present a new avenue of therapies to treat spinal cord injuries.”
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Psoriasis is a chronic and recurrent inflammatory skin disease and its histological features are characterized by epidermal hyperplasia, increased angiogenesis and immune cell infiltration. Psoriasis prevalence is about 0.1%-3%, affecting approximately 125 million people worldwide. In China, there are about 10 million psoriasis patients.
Human umbilical cord-derived MSC (huc-MSC) has many advantages for the treatment of immune disease. Because it was demonstrated that huc-MSCs are effective in modulating immune cells and treating diseases and it has low immunogenicity. Furthermore, huc-MSCs do not raise ethical issue for clinical applications.
Some experimental results and cases has showed that mesenchymal stem cell (MSC) can prevent or treat psoriasis. This clinical study is conducted to provide more data to evaluate the effect and safety of treatment of psoriasis by human umbilical cord-derived mesenchymal stem cell.
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